Interstitial Lung DiseaseInterstitial Lung Disease

Kunwar Sohal, PGY3Kunwar Sohal, PGY3

2/3/20102/3/2010

Idiopathic Interstitial Idiopathic Interstitial Pneumonias Pneumonias

• Subset of diffuse interstitial lung diseases of Subset of diffuse interstitial lung diseases of unknown etiology characterized by expansion unknown etiology characterized by expansion of the interstitial compartment w/an infiltrate of the interstitial compartment w/an infiltrate of inflammatory cellsof inflammatory cells sometimes sometimes accompanied by fibrosis, either in the form of accompanied by fibrosis, either in the form of abnormal collagen deposition or proliferation abnormal collagen deposition or proliferation of fibroblasts capable of collagen synthesis of fibroblasts capable of collagen synthesis

• All under umbrella of IPF? Or separated based All under umbrella of IPF? Or separated based on histological appearance? Matter of debateon histological appearance? Matter of debate

Averill LiebowAverill Liebow

• Pioneered the notion that morphologic characteristics are Pioneered the notion that morphologic characteristics are useful in separating idiopathic interstitial pneumonias into useful in separating idiopathic interstitial pneumonias into clinically and histologically distinct groups clinically and histologically distinct groups

• These processes were histological patterns rather than free These processes were histological patterns rather than free standing diagnostic entities, and that each could occur in a standing diagnostic entities, and that each could occur in a variety of clinical contexts variety of clinical contexts

• Maintained that precise histological classification of Maintained that precise histological classification of interstitial pneumonias provides clues to etiology, interstitial pneumonias provides clues to etiology, pathogenesis, natural history, and prognosis (helps limit pathogenesis, natural history, and prognosis (helps limit differential dx and lead to treatment options and response)differential dx and lead to treatment options and response)

• The biopsy is intended not only to confirm the suspicion of The biopsy is intended not only to confirm the suspicion of an interstitial pneumonia, but also to exclude various IPF an interstitial pneumonia, but also to exclude various IPF mimics such as sarcoidosis, hypersensitivity pneumonitis, mimics such as sarcoidosis, hypersensitivity pneumonitis, and pulmonary Langerhans' cell histiocytosis and pulmonary Langerhans' cell histiocytosis

UIP-Usual Interstitial UIP-Usual Interstitial Pneumonia Pneumonia • IPF - a specific form of chronic fibrosing interstitial IPF - a specific form of chronic fibrosing interstitial

pneumonia limited to the lung and associated with pneumonia limited to the lung and associated with the histologic appearance of usual interstitial the histologic appearance of usual interstitial pneumonia (UIP) based on surgical biopsypneumonia (UIP) based on surgical biopsy

• IPF has an estimated prevalence of 14 to 43 per IPF has an estimated prevalence of 14 to 43 per 100,000100,000

• Most cases are sporadic and present with slowly Most cases are sporadic and present with slowly progressive dyspnea and nonproductive cough progressive dyspnea and nonproductive cough

• Prevalence and incidence increase with agePrevalence and incidence increase with age• HRCT demonstrates a characteristic pattern of HRCT demonstrates a characteristic pattern of

peripheral (subpleural) and bibasilar reticulonodular peripheral (subpleural) and bibasilar reticulonodular opacities associated with architectural distortion, opacities associated with architectural distortion, including honeycomb changes and traction including honeycomb changes and traction bronchiectasis bronchiectasis

HistoHisto• Histologic hallmark and chief diagnostic criterion is a Histologic hallmark and chief diagnostic criterion is a

heterogeneous appearance with alternating areas of heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibroblast foci, and normal lung, interstitial inflammation, fibroblast foci, and honeycomb change honeycomb change

• The tissue is stained with hematoxylin (purple dye) and The tissue is stained with hematoxylin (purple dye) and eosin (pink dye) to make it visible. The pink areas in this eosin (pink dye) to make it visible. The pink areas in this picture represent lung fibrosis (patchwork fibrosis)picture represent lung fibrosis (patchwork fibrosis)

• Honeycombing, traction Honeycombing, traction bronchiectasis, predominance in bronchiectasis, predominance in bases, mild mediastinal LADbases, mild mediastinal LAD

RB-ILD Respiratory RB-ILD Respiratory bronchiolitis-associated bronchiolitis-associated interstitial lung disease interstitial lung disease • Also uncommon, accounting for only 2 percent of Also uncommon, accounting for only 2 percent of

biopsied Mayo Clinic patients who were suspected biopsied Mayo Clinic patients who were suspected of having IPFof having IPF

• DIP and RB-ILD show significant clinical, DIP and RB-ILD show significant clinical, radiologic and histologic overlap, and in some radiologic and histologic overlap, and in some patients the distinction is arbitrary and of patients the distinction is arbitrary and of uncertain clinical significance uncertain clinical significance

• Clinical features are non-specific, usually males, Clinical features are non-specific, usually males, smokers, 30+ pk year hx, symptoms are usually smokers, 30+ pk year hx, symptoms are usually mild and not disabling mild and not disabling

• Chest radiographs are abnormal in 80 percent of Chest radiographs are abnormal in 80 percent of patients and show diffuse fine reticular or patients and show diffuse fine reticular or reticulonodular opacities in a bibasilar distribution reticulonodular opacities in a bibasilar distribution

HistoHisto

• The main feature that distinguishes DIP from RB-The main feature that distinguishes DIP from RB-ILD is that DIP affects the lung in a more uniform ILD is that DIP affects the lung in a more uniform and diffuse manner, lacking the bronchiolocentric and diffuse manner, lacking the bronchiolocentric distribution of macrophages seen in RB-ILD distribution of macrophages seen in RB-ILD

• It is likely that DIP and RB-ILD are highly related if It is likely that DIP and RB-ILD are highly related if not identical lesions, differing only in the severity not identical lesions, differing only in the severity and extent of the abnormality (ie, RB-ILD = and extent of the abnormality (ie, RB-ILD = mild/early DIP). mild/early DIP).

• Pertinent NEG findings: Lack of diffuse Pertinent NEG findings: Lack of diffuse macrophage accumulation, and interstitial fibrosis macrophage accumulation, and interstitial fibrosis and/or honeycomb fibrosis and/or honeycomb fibrosis

• Diffuse ground glass Diffuse ground glass abnormality, with abnormality, with some associated some associated cystic changes cystic changes

• Bronchial wall Bronchial wall thickening (arrow-thickening (arrow-thickened interlobular thickened interlobular septa)septa)

DIP-Desquamative Interstitial DIP-Desquamative Interstitial Pneumonia Pneumonia • It is relatively uncommon, comprising 8 percent of biopsied Mayo It is relatively uncommon, comprising 8 percent of biopsied Mayo

Clinic patients suspected of having IPFClinic patients suspected of having IPF• The vast majority (>90 percent) of patients with DIP are smokers, The vast majority (>90 percent) of patients with DIP are smokers,

a small percentage of cases are associated with connective tissue a small percentage of cases are associated with connective tissue diseases diseases

• Glucocorticoids are beneficial in the majority of patients, and the Glucocorticoids are beneficial in the majority of patients, and the overall survival is about 70 percent after 10 years  overall survival is about 70 percent after 10 years 

• Radiographic abnormalities: less severe than UIP, HRCT shows Radiographic abnormalities: less severe than UIP, HRCT shows ground glass opacities without the peripheral reticular and ground glass opacities without the peripheral reticular and reticulonodular opacities characteristic of UIP reticulonodular opacities characteristic of UIP

• One review of HRCT findings found no evidence of progression One review of HRCT findings found no evidence of progression from DIP to UIP, further supporting the concept that DIP and UIP from DIP to UIP, further supporting the concept that DIP and UIP are separate and distinct entities (Chest, 1996)are separate and distinct entities (Chest, 1996)

• DIP differs histologically from UIP in that the changes tend to be DIP differs histologically from UIP in that the changes tend to be much more uniform at low magnification much more uniform at low magnification

• The most striking feature is the presence of numerous The most striking feature is the presence of numerous mononuclear cells within most of the distal air spaces. These mononuclear cells within most of the distal air spaces. These mononuclear cells represent smokers' macrophages rather than mononuclear cells represent smokers' macrophages rather than desquamated pneumocytes, as had been originally proposed desquamated pneumocytes, as had been originally proposed

HistoHisto

• The alveoli are The alveoli are filled with filled with macrophages macrophages containing brown containing brown pigment in this pigment in this disease of disease of smokers.smokers.

• Tx: smoking Tx: smoking cessation, cessation, steroidssteroids

AIP-Acute Interstitial AIP-Acute Interstitial Pneumonia Pneumonia • Etiology: neutrophil mediated lung injuryEtiology: neutrophil mediated lung injury• Initial stage: inc capillary permeability, leads to organizing stage Initial stage: inc capillary permeability, leads to organizing stage

with fibroblast prolif (can progress to severe fibrosis)with fibroblast prolif (can progress to severe fibrosis)• Presents with the explosive onset of respiratory symptoms and is Presents with the explosive onset of respiratory symptoms and is

characterized by rapidly progressive respiratory failure characterized by rapidly progressive respiratory failure associated with diffuse infiltrates on chest radiographs (versus associated with diffuse infiltrates on chest radiographs (versus chronic nature of others)chronic nature of others)

• This acute variant is analogous to the acute respiratory distress This acute variant is analogous to the acute respiratory distress syndrome (ARDS), differing only in that it is not preceded by a syndrome (ARDS), differing only in that it is not preceded by a catastrophic event, it is idiopathiccatastrophic event, it is idiopathic

• Other terms have been proposed: including Hamman-Rich Other terms have been proposed: including Hamman-Rich syndrome and accelerated interstitial pneumonia syndrome and accelerated interstitial pneumonia

• AIP has the same poor prognosis as ARDS, and the majority of AIP has the same poor prognosis as ARDS, and the majority of patients die of respiratory failure patients die of respiratory failure

• Digital clubbing is limited to patients with acute exacerbation of Digital clubbing is limited to patients with acute exacerbation of underlying fibrotic lung disease and serves as a helpful clue to underlying fibrotic lung disease and serves as a helpful clue to separate such patients from those with AIP separate such patients from those with AIP

HistoHisto

• AIP is identical to the organizing or AIP is identical to the organizing or proliferative stage of diffuse alveolar proliferative stage of diffuse alveolar damage (DAD) damage (DAD)

• The main finding is extensive The main finding is extensive interstitial fibroblast proliferation interstitial fibroblast proliferation within an edematous-appearing within an edematous-appearing stroma stroma

• Classical histopathology of DAD is evident with prominent hyaline Classical histopathology of DAD is evident with prominent hyaline membranes (hm) lining alveolar spaces. membranes (hm) lining alveolar spaces.

• Note that the interstitium of the lung is thickened and Note that the interstitium of the lung is thickened and hypercellular. While hyaline membranes are still present, 1-4 days hypercellular. While hyaline membranes are still present, 1-4 days after the acute injury event, the interstitium is edematous and has after the acute injury event, the interstitium is edematous and has sparse inflammatory cells sparse inflammatory cells

HRCTHRCT

• Characteristics are diffuse orCharacteristics are diffuse or patchy consolidation patchy consolidation • HRCT findings in AIP are HRCT findings in AIP are

indistinguishable from ARDS indistinguishable from ARDS • Sometimes bilateral areas of Sometimes bilateral areas of

airspace consolidation in a airspace consolidation in a predominantly subpleural predominantly subpleural distribution. Mild distribution. Mild honeycombing, usually honeycombing, usually affecting < 10% of the lung, affecting < 10% of the lung, may be present may be present

• Traction bronchiectasis is often Traction bronchiectasis is often seen as a delayed seen as a delayed manifestation in the areas of manifestation in the areas of air-space consolidation or air-space consolidation or ground-glass attenuation ground-glass attenuation

NSIP-Nonspecific Interstitial NSIP-Nonspecific Interstitial Pneumonia Pneumonia • Chronic interstitial pneumonia that lacks the Chronic interstitial pneumonia that lacks the

histopathologic features typical of UIP, DIP, RB-ILD or AIP histopathologic features typical of UIP, DIP, RB-ILD or AIP • In studies of idiopathic pulmonary fibrosis, NSIP has been In studies of idiopathic pulmonary fibrosis, NSIP has been

described as "early" or "cellular" UIP (“fibrosing” NSIP described as "early" or "cellular" UIP (“fibrosing” NSIP behaves like IPF-more fibrotic foci, worse outcome)behaves like IPF-more fibrotic foci, worse outcome)

• The most important clinical characteristics that distinguish The most important clinical characteristics that distinguish NSIP from UIP are a subacute rather than insidious onset of NSIP from UIP are a subacute rather than insidious onset of symptoms, associated fever in about one-third of patients, symptoms, associated fever in about one-third of patients, lack of a strong male predominance, relative absence of lack of a strong male predominance, relative absence of clubbing in NSIP, and increased frequency of features clubbing in NSIP, and increased frequency of features suggestive of connective tissue disease suggestive of connective tissue disease

• As the name implies, the histological findings in patients As the name implies, the histological findings in patients with NSIP are variable with NSIP are variable

• The main change in all cases is an interstitial pneumonia The main change in all cases is an interstitial pneumonia characterized by expansion of alveolar septa by a variably characterized by expansion of alveolar septa by a variably dense infiltrate of predominantly mononuclear dense infiltrate of predominantly mononuclear inflammatory cells with or without associated fibrosis inflammatory cells with or without associated fibrosis

HRCTHRCT

• HRCT findings include HRCT findings include bilateral patchy ground-bilateral patchy ground-glass attenuation, glass attenuation, bilateral areas of bilateral areas of consolidation, irregular consolidation, irregular lines, and bronchial lines, and bronchial dilatation. Ground-glass dilatation. Ground-glass attenuation is the attenuation is the predominant finding in predominant finding in most cases and is the most cases and is the sole abnormality in sole abnormality in about 1/3 of cases about 1/3 of cases

• Bilateral subpleural Bilateral subpleural ground-glass opacities ground-glass opacities (arrowhead) and (arrowhead) and irregular linear opacities irregular linear opacities (arrow) (arrow)

NSIP contdNSIP contd

• Groups: I, II: majority of patients had a Groups: I, II: majority of patients had a prominent inflammatory component either prominent inflammatory component either without (Group I) or with (Group II) without (Group I) or with (Group II) concomitant fibrosis; biopsies showing concomitant fibrosis; biopsies showing predominantly fibrosis (Group III) were the predominantly fibrosis (Group III) were the least common least common

• As noted in other studies, the most As noted in other studies, the most compelling distinction between NSIP and compelling distinction between NSIP and UIP was related to outcome: NSIP had a UIP was related to outcome: NSIP had a significantly better prognosis than UIP significantly better prognosis than UIP

Treatment and Prognosis of Treatment and Prognosis of Idiopathic Interstitial Idiopathic Interstitial Pneumonias Pneumonias • Idiopathic pulmonary fibrosis: Possibly lung Idiopathic pulmonary fibrosis: Possibly lung

transplantation, Mortality rate: 50–70% in 3 transplantation, Mortality rate: 50–70% in 3 yryr

• NS-IP: Corticosteroids, Mortality rate: < 10% NS-IP: Corticosteroids, Mortality rate: < 10% 5yr5yr

• RB-ILD: Smoking cessation, Mortality: rareRB-ILD: Smoking cessation, Mortality: rare• DIP: Smoking cessation, Mortality rate: 5% in DIP: Smoking cessation, Mortality rate: 5% in

5 yr5 yr• AIP: Best tx unknown, Mortality rate: 60% AIP: Best tx unknown, Mortality rate: 60%

in <6 mo (Corticosteroid therapy is generally in <6 mo (Corticosteroid therapy is generally used, but efficacy has not been established)used, but efficacy has not been established)

BOOP/COP?BOOP/COP?

• Cryptogenic organizing pneumonitis Cryptogenic organizing pneumonitis (COP), which is the name applied to (COP), which is the name applied to the idiopathic form of organizing the idiopathic form of organizing pneumonia (idiopathic BOOP), is a pneumonia (idiopathic BOOP), is a distinct clinical entity with features of distinct clinical entity with features of a pneumonia rather than a primary a pneumonia rather than a primary airway disorderairway disorder

ApproachApproach

• History, family history, occupational hx, exposures, syms, labs, History, family history, occupational hx, exposures, syms, labs, rads, PFTs, etc.rads, PFTs, etc.

• Role of lung biopsy: Not possible to make a definitive diagnosis or Role of lung biopsy: Not possible to make a definitive diagnosis or to stage the disease without careful examination of lung tissue to stage the disease without careful examination of lung tissue

• Indications for performing a lung biopsy:Indications for performing a lung biopsy:– To provide a specific diagnosis, especially in a patient with atypical or To provide a specific diagnosis, especially in a patient with atypical or

progressive symptoms and signs, or rapid clinical deterioration or progressive symptoms and signs, or rapid clinical deterioration or sudden change in radiographic appearance sudden change in radiographic appearance

– To assess disease activity To assess disease activity – To exclude neoplastic and infectious processes that occasionally mimic To exclude neoplastic and infectious processes that occasionally mimic

chronic, progressive interstitial disease chronic, progressive interstitial disease – To identify a more treatable process than originally suspected To identify a more treatable process than originally suspected – To establish a definitive diagnosis and predict prognosis before To establish a definitive diagnosis and predict prognosis before

proceeding with therapies which may have serious side effects proceeding with therapies which may have serious side effects

• Transbronchial lung biopsy: Normal tissue or nonspecific changes Transbronchial lung biopsy: Normal tissue or nonspecific changes on transbronchial lung biopsy may result from a sampling error, on transbronchial lung biopsy may result from a sampling error, need larger sample (VATS preferred method)need larger sample (VATS preferred method)